Now, French researchers have designed a decoy version of fibroblast growth factor receptor 3
(FGFR3; CD333) that increased bone
length and decreased achondroplasia-associated complications in mice compared
with vehicle.1 The molecule has a longer half-life than other
clinical candidates focused on correcting abnormal signaling by FGFR3.

Achondroplasia is the most common form of short-limb
dwarfism. The genetic disorder is caused by a gain-of-function point mutation
in FGFR3 that prolongs ligand binding to the receptor and delays
receptor internalization, thus increasing FGFR3 signaling.

Achondroplasia research has turned toward correcting the
abnormal FGFR3 signaling in children. Last year, one such treatment from BioMarin Pharmaceutical Inc.
began clinical testing.

The company's BMN-111 is an analog of C-type natriuretic peptide (CNP; NPPC) that blocks signaling
downstream of FGFR3 in the growth plate. The molecule has completed a Phase I
trial in healthy adults, and BioMarin hopes to begin a Phase II trial in
patients this year or in 1Q14.

In animal models, BMN-111 was safe and restored bone growth
during the growth period, resulting in bones of normal length. The compound has
a half-life of 45 minutes, which VP of Pharmacological Sciences Charles O'Neill
said may require daily dosing.

Now, Elvire Gouze and colleagues at Institut National de la Santé et de la Recherche Médicale
U1065 (INSERM U1065) have taken a different
approach to blocking aberrant FGFR3 signaling in achondroplasia. The team
designed a soluble human FGFR3 (sFGFR3)
receptor that acts as a decoy for FGFR3 ligands to decrease ligand binding and
receptor signaling.

In a mouse model of achondroplasia, the team subcutaneously
injected 0.25 or 2.5 mg/kg of sFGFR3 twice weekly for three weeks in newborn
mice.

The animals had increased skeletal growth and long-bone length and
decreased mortality compared with vehicle-treated controls. Bone length in treated
mice was comparable to that in healthy controls.

sFGFR3 also penetrated the cartilage matrix of the growth
plate, stimulated chondrocyte maturation and increased synthesis of
extracellular matrix components. These findings suggest that sFGFR3 restores
chondrocyte maturation blocked by the aberrant sFGFR3 activation in
achondroplasia.

The next question was whether sFGFR3 could correct achondroplasia's
effects on spinal and skull abnormalities. Whereas 80% of vehicle-treated mice
had spinal deformities, only 12% and 6% of mice receiving low and high sFGFR3
doses, respectively, developed abnormalities.

sFGFR3 also corrected skull length. The molecule was safe
and had a half-life of about 16 hours in mice.

Data were published in Science Translational Medicine.

"Our treatment was effective at both restoring the
stature of treated mice and preventing complications. This was critical for the
treatment to have benefits over existing approaches," said Gouze.

"This strategy may also work as a treatment for very
severe complications that occur due to FGFR3 mutations, such as severe
achondroplasia with developmental delay and acanthosis nigricans, which is
characterized by extremely short stature and intellectual disability,"
said Kalina Hristova, professor of materials science and biomedical engineering
at The Johns Hopkins University.

Halftime

Gouze said that her team needs to verify
that sFGFR3's half-life in humans is at least equivalent to that in mice.

She added, "We cannot plan a dosing regimen in humans
as we need to verify the pharmacokinetic parameters in humans first. We can
just say that it would certainly not be daily injections."

O'Neill acknowledged that sFGFR3 has a longer half-life and
the potential for less frequent dosing. However, he noted that "this could
be a good and a bad thing. If any toxicities do arise from treatment with
sFGFR3, it would take longer to resolve the toxicological response. In
comparison, we have found that normal bone growth patterns are restored within
one week of cessation of treatment with BMN-111."

O'Neill also said that decoy receptors "have the
potential to cause immunogenicity issues, especially when tested in higher
species. Antibodies against the protein could decrease the therapeutic benefit
and could also cause toxicity issues if there is any cross-reactivity for
related human receptors."

He wanted to see mice dosed with sFGFR3 for longer periods
of time to characterize any immunogenicity and cross-reactivity for endogenous FGFRs.

O'Neill said that BioMarin has seen a weak immunological
response to BMN-111 in animal studies, but the presence of antibodies did not
affect the pharmacological activity of the drug or the safety profile. BMN-111
is 39 amino acids long, whereas sFGFR3 is about 700 amino acids long.

Hristova added that the use of a full-length protein could
also be associated with high costs.

"The authors use the full-length extracellular domain
of FGFR3 and produce it in mammalian cells. This treatment may be too
expensive, especially if long-term therapy is required. It should be
investigated if the post-translational modifications of the soluble FGFR3 are
required for this application. If they are not, it may be possible to produce
the protein in bacteria in a cost-effective way," she said.

Finally, O'Neill noted the large amount of sFGFR3 needed
for therapeutic activity. "The molecular characteristics of sFGFR3 don't
favor movement to the growth plate," which is a cartilage component at the
end of bones in children and adolescents that is involved in initial
development and growth. "This could be the reason that high doses are
required for therapeutic effect in the mice, and the researchers may need to
tweak the molecule to allow easier distribution to the growth plate."

Gouze told SciBX that INSERM U1065 has filed an
international patent application and that the IP is available for licensing.

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